The Statisticians Role in

Pharmaceutical Development
Steps in the process
 Compound delivered from Discovery
 Early studies
 Pre Clinical
 Clinical
 Development for market launch
 Regulatory Submission Approval
 Life Cycle Management
Organization of talk
 Overview of the process step
 Statistician’s role
 Responsibilities
 Statistics at AstraZeneca
Discovery Step
 Targeted development
 Clinical unmet medical
need
 Seek series of molecules
that hit target
 Select candidates which
have desired activity
 Test molecules to
quantify effect on target
Target identification
 What is needed?
 What features are
desired?
 What is acceptable in
terms of risk?
 Cross functional team
comes up with a
Target Product
Profile
Statisticians Role (high level, experienced)
 Provide scientific method thinking into the target
evaluation process
 Assess the ability to Quantify effect on target of
interest
 Does animal model translate into human
 How will effective dose be identified
 Provide critical input into quantification of risk
 Assist in establishing go/no go decision criteria
Challenges
 Cross functional team members have different
goals and needs
 Statistician needs to be aware of competing needs
of stake holders
 Clinical – elegant science, meeting patient needs
 Commercial – optimum product to sell
 Business – speed to market
 Translational science may be in infancy, signal in
animal model not validated in human disease
Early Clinical Stage
 Pharmacokinetics
 Dose finding
 Single ascending dose
 Multiple ascending dose

 Metabolism and elimination

 Drug interaction studies
Early Clinical Stage
 Is the compound safe
enough to dose in an
effective range
 What are the kinetic
properties
 Linear dose response
 Accumulation on
multiple dosing
Statistical responsibilities
 Review of margins from animal data
 Agree criteria for stopping dose escalation
 Plan for Go/No go decision
 Ensure program assesses areas of potential
safety risk identified in animal tox studies
Challenges
 Relatively small sample sizes in studies
 Decisions based more on clinical judgment
than statistics
 Study designs critical at this stage
 Need to get buy in for decision rules put in
place
Development for Market Launch
 Clinical Development Plan
 What needs to be done to support desired
claims in world markets (Regulatory
requirements)
 What trials, which drug interaction studies
 What are the competitors and their profiles
 Is there something we can demonstrate value for
the patient (efficacy or safety)
Aspects of development for
market
 Proof of concept
 Dose selection
 Confirmatory studies (minimum of 2)
 Long term safety studies
 Studies based on propertied of drug
 Thorough QT study for ECG changes
 Interaction studies based on concomitant use
or metabolic pathway
Statistical responsibilities in
development phase
 Study design decisions
 Selection of Primary
endpoints for studies
 Risk assessment
 need to adjust for
multiple comparisons?
 Interim analyses
 Quantification of
decision criteria
 Data Monitoring Boards
Challenges
 Statistics represented at several levels
 Ensuring one voice (consistency)
 Regulatory guidelines in place
 Can change during development
 Differ across regions
 Need to be aware of the environment
 High visibility – failures due to incorrect
assumptions are a problem
 Clinical and Commercial input may differ
 Need good negotiation skills
Regulatory submission and
approval
 Synthesize the data
 Provide thorough
structure description
 Provide standardized
information in agreed
format
 Support the package
 Agree the label
Statistical Responsibility
 Provide plan to synthesize the data across the
program
 Ensure that the data is clearly reported and
statements are supported by appropriate statistical
analysis
 Prepare for questions which may come during
review
 Prepare presentation for Advisory panel if needed
 Review label language and address regulatory
issues in label
Challenges
 Work as integral part of a larger team – need to
reach consensus on issues
 Commercial and drug safety have more influence
in this stage – need to be able to clarify the
statistical issues for non-statisticians
 Need to be able to provide information in a way
that facilitates the benefit/risk assessment
 In labeling negotiations need to be aware of who
the target audience for the label is
Life Cycle Management
 Product is on the market
 How to we maximize it’s value
 Broaden the indications for use
 Identify patients currently not treated

 Look for ways to demonstrate the strength of the

product compared to others
 Look for economic or quality of life benefits
Statistician’s responsibilities
 Review of Ideas for studies supplied by
outside researchers
 Mine registration data to identify scientific
questions we have a reasonable chance of
addressing
 Assist in developing plan for new clinical
indications
 Evaluate the development risks
Statistical Positions and Roles at AstraZeneca
 Statistician – usually study statistician
 Study Design Concept Plan to protocol
 Provides link between objectives and variables
 Provides design and sample size justification
 Contributes the statistical analysis
 Writes Statistical analysis plan
 detail document for data handling and analysis
 Performs analysis and supports the interpretation of
results
 Contributes to Study report and publications and
presentations of the data
Statistical Positions and Roles at AstraZeneca

 Senior Statistician
 Supports Project (several studies at once)
 Study statistician responsibilities
 Leads delivery teams – project management
as well as statistical responsibilities
 Cross functional leadership
 Mentor or coach statistician level
Statistical Positions and Roles at AstraZeneca
 Principal Statistician
 Supports Program (several studies at once)
 Oversees the work of Study statistician delivering
a program of work
 Provides Analysis Plan for project level as
template for individual studies
 Starts to work more closely with the Global
team on risk assessment and mitigation plans
 Uses experience and statistical knowledge to
facilitate quantification of risk
Statistical Positions and Roles at AstraZeneca

 Statistician Science Director

 Biostatistics leadership within the company
 May have research or other key initiative activities
for the company
 Project leadership roles
 Global Product Statistician
 Therapeutic area Global Statistician
Statistical Positions and Roles at AstraZeneca
 Global Product Statistician
 Input into the Clinical Development Plan
 Review responsibilities for all study protocols,
statistical analysis plans, and documents sent to
regulatory authorities
 Represent statistics for a product in any regulatory
interactions
 Strategic review of data as it comes in to identify
aspects of the drug (risk or benefits)
 Support the Commercial function by providing
scientific approach and clarity around messages
Statistical Positions and Roles at AstraZeneca
 Therapeutic Area Global Statistician
 Input into the early stage compounds
 Keep abreast of the literature to ensure that
advice is appropriate
 Look at the data in the industry landscape to
assess development risks
 Support the Commercial function by
providing scientific approach and clarity
around possibilities given current knowledge
Thank you